tbuckley/cabot-search huggingface dataset:
Sequencing of Ipilimumab Plus Nivolumab and Encorafenib Plus Binimetinib for Untreated <i>BRAF</i>-Mutated Metastatic Melanoma (SECOMBIT): A Randomized, Three-Arm, Open-Label Phase II Trial
Authors: Paolo A. Ascierto, Mario Mandalà, Pier Francesso Ferrucci, Massimo Guidoboni, Piotr Rutkowski, Virginia Ferraresi, Ana Arance, Michele Guida, Evaristo Maiello, Helen Gogas, Erika Richtig, Maria Teresa Fierro, Celeste Lebbè, Hildur Helgadottir, Paola Queirolo, Francesco Spagnolo, Marco Tucci, Michele Del Vecchio, Maria Gonzales Cao, Alessandro Marco Minisini, Sabino De Placido, Miguel F. Sanmamed, Domenico Mallardo, Marcello Curvietto, Ignacio Melero, Giuseppe Palmieri, Antonio M. Grimaldi, Diana Giannarelli, Reinhard Dummer, Vanna Chiarion Sileni
Journal: Journal of Clinical Oncology (2022)

Limited prospective data are available on sequential immunotherapy and BRAF/MEK inhibition for BRAFV600-mutant metastatic melanoma.SECOMBIT is a randomized, three-arm, noncomparative phase II trial (ClinicalTrials.gov identifier: NCT02631447). Patients with untreated, metastatic BRAFV600-mutant melanoma from 37 sites in nine countries were randomly assigned to arm A (encorafenib [450 mg orally once daily] plus binimetinib [45 mg orally twice daily] until progressive disease [PD] -> ipilimumab plus nivolumab [ipilimumab 3 mg/kg once every 3 weeks and nivolumab 1 mg/kg once every 3 weeks × four cycles -> nivolumab 3 mg/kg every 2 weeks]), arm B [ipilimumab plus nivolumab until PD -> encorafenib plus binimetinib], or arm C (encorafenib plus binimetinib for 8 weeks -> ipilimumab plus nivolumab until PD -> encorafenib plus binimetinib). The primary end point was overall survival (OS) at 2 years. Secondary end points included total progression-free survival, 3-year OS, best overall response rate, duration of response, and biomarkers in the intent-to-treat population. Safety was analyzed throughout sequential treatment in all participants who received at least one dose of study medication.A total of 209 patients were randomly assigned (69 in arm A, 71 in arm B, and 69 in arm C). At a median follow-up of 32.2 (interquartile range, 27.9-41.6) months, median OS was not reached in any arm and more than 30 patients were alive in all arms. Assuming a null hypothesis of median OS of ≤ 15 months, the OS end point was met for all arms. The 2-year and 3-year OS rates were 65% (95% CI, 54 to 76) and 54% (95% CI, 41 to 67) in arm A, 73% (95% CI, 62 to 84) and 62% (95% CI, 48 to 76) in arm B, and 69% (95% CI, 59 to 80) and 60% (95% CI, 58 to 72) in arm C. No new safety signals emerged.Sequential immunotherapy and targeted therapy provide clinically meaningful survival benefits for patients with BRAFV600-mutant melanoma.
Ultrasound‐Enhanced Antibacterial Activity of Polymeric Nanoparticles for Eradicating Bacterial Biofilms
Authors: Sanjana Gopalakrishnan, Aarohi Gupta, Jessa M. V. Makabenta, Jungmi Park, John J. Amante, Aritra Nath Chattopadhyay, Dorcas Matuwana, Cathal J. Kearney, Vincent M. Rotello
Journal: Advanced Healthcare Materials (2022)

Bacterial biofilms are a major healthcare concern resulting in refractory conditions such as chronic wounds, implant infections and failure, and multidrug-resistant infections. Aggressive and invasive strategies are employed to cure biofilm infections but are prone to long and expensive treatments, adverse side-effects, and low patient compliance. Recent strategies such as ultrasound-based therapies and antimicrobial nanomaterials have shown some promise in the effective eradication of biofilms. However, maximizing therapeutic effect while minimizing healthy tissue damage is a key challenge that needs to be addressed. Here a combination treatment involving ultrasound and antimicrobial polymeric nanoparticles (PNPs) that synergistically eradicate bacterial biofilms is reported. Ultrasound treatment rapidly disrupts biofilms and increases penetration of antimicrobial PNPs thereby enhancing their antimicrobial activity. This results in superior biofilm toxicity, while allowing for a two- to sixfold reduction in both the concentration of PNPs as well as the duration of ultrasound. Furthermore, that this reduction minimizes cytotoxicity toward fibroblast cells, while resulting in a 100- to 1000-fold reduction in bacterial concentration, is demonstrated.
Farnesyltransferase inhibitor LNK-754 attenuates axonal dystrophy and reduces amyloid pathology in mice
Authors: Leah K. Cuddy, Alia O. Alia, Miranda A. Salvo, Sidhanth Chandra, Tom N. Grammatopoulos, Craig J. Justman, Peter T. Lansbury, Joseph R. Mazzulli, Robert Vassar
Journal: Molecular Neurodegeneration (2022)

Abstract Background Amyloid plaque deposition and axonal degeneration are early events in AD pathogenesis. Aβ disrupts microtubules in presynaptic dystrophic neurites, resulting in the accumulation of impaired endolysosomal and autophagic organelles transporting β-site amyloid precursor protein cleaving enzyme (BACE1). Consequently, dystrophic neurites generate Aβ42 and significantly contribute to plaque deposition. Farnesyltransferase inhibitors (FTIs) have recently been investigated for repositioning toward the treatment of neurodegenerative disorders and block the action of farnesyltransferase (FTase) to catalyze farnesylation, a post-translational modification that regulates proteins involved in lysosome function and microtubule stability. In postmortem AD brains, FTase and its downstream signaling are upregulated. However, the impact of FTIs on amyloid pathology and dystrophic neurites is unknown. Methods We tested the effects of the FTIs LNK-754 and lonafarnib in the 5XFAD mouse model of amyloid pathology. Results In 2-month-old 5XFAD mice treated chronically for 3 months, LNK-754 reduced amyloid plaque burden, tau hyperphosphorylation, and attenuated the accumulation of BACE1 and LAMP1 in dystrophic neurites. In 5-month-old 5XFAD mice treated acutely for 3 weeks, LNK-754 reduced dystrophic neurite size and LysoTracker-Green accumulation in the absence of effects on Aβ deposits. Acute treatment with LNK-754 improved memory and learning deficits in hAPP/PS1 amyloid mice. In contrast to LNK-754, lonafarnib treatment was less effective at reducing plaques, tau hyperphosphorylation and dystrophic neurites, which could have resulted from reduced potency against FTase compared to LNK-754. We investigated the effects of FTIs on axonal trafficking of endolysosomal organelles and found that lonafarnib and LNK-754 enhanced retrograde axonal transport in primary neurons, indicating FTIs could support the maturation of axonal late endosomes into lysosomes. Furthermore, FTI treatment increased levels of LAMP1 in mouse primary neurons and in the brains of 5XFAD mice, demonstrating that FTIs stimulated the biogenesis of endolysosomal organelles. Conclusions We show new data to suggest that LNK-754 promoted the axonal trafficking and function of endolysosomal compartments, which we hypothesize decreased axonal dystrophy, reduced BACE1 accumulation and inhibited amyloid deposition in 5XFAD mice. Our results agree with previous work identifying FTase as a therapeutic target for treating proteinopathies and could have important therapeutic implications in treating AD.
The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: Guidelines for reporting observational studies
Authors: Erik von Elm, Douglas G. Altman, Matthias Egger, Stuart J. Pocock, Peter C. Gøtzsche, Jan P. Vandenbroucke
Journal: International Journal of Surgery (2014)

Much biomedical research is observational. The reporting of such research is often inadequate, which hampers the assessment of its strengths and weaknesses and of a study's generalisability. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Initiative developed recommendations on what should be included in an accurate and complete report of an observational study. We defined the scope of the recommendations to cover three main study designs: cohort, case–control, and cross-sectional studies. We convened a 2-day workshop in September 2004, with methodologists, researchers, and journal editors to draft a checklist of items. This list was subsequently revised during several meetings of the coordinating group and in e-mail discussions with the larger group of STROBE contributors, taking into account empirical evidence and methodological considerations. The workshop and the subsequent iterative process of consultation and revision resulted in a checklist of 22 items (the STROBE Statement) that relate to the title, abstract, introduction, methods, results, and discussion sections of articles. 18 items are common to all three study designs and four are specific for cohort, case–control, or cross-sectional studies. A detailed Explanation and Elaboration document is published separately and is freely available on the Web sites of PLoS Medicine, Annals of Internal Medicine, and Epidemiology. We hope that the STROBE Statement will contribute to improving the quality of reporting of observational studies.
pH-activated nanoplatform for visualized photodynamic and ferroptosis synergistic therapy of tumors
Authors: Rui Sun, Wen Ma, Mingjian Ling, Chenhong Tang, Min Zhong, Jingyue Dai, Meiyan Zhu, Xuzi Cai, Guang Li, Qing Xu, Longguang Tang, Zhiqiang Yu, Zhenwei Peng
Journal: Journal of Controlled Release (2022)
A case of early esophageal cancer with pharyngeal stenosis treated by endoscopic submucosal multi-tunnel dissection using an ultra-thin endoscope
Authors: Kohei Ono, Ken Ohata, Yoshiaki Kimoto, Rindo Ishii, Ryoju Negishi, Yohei Minato, Takashi Muramoto
Journal: Endoscopy (2022)

A 70-year-old man presented with early-stage esophageal cancer located in a semicircle in the upper esophagus. The hypopharynx was getting narrower owing to postoperative chemoradiotherapy for past pharyngeal cancer, and it was impossible to pass the pyriform sinus using a conventional scope. Therefore, we performed endoscopic submucosal multi-tunnel dissection, which has been shown to be effective for large esophageal cancers
The “straighten pigtail” technique for selective replacement of a pigtail plastic stent
Authors: Mamoru Takenaka, Tomohiro Fukunaga, Akihiro Yoshida, Shunsuke Omoto, Masatoshi Kudo
Journal: Endoscopy (2022)

In cases of malignant hilar biliary obstruction (MHBO), a biliary stent should be selectively placed in the biliary branch where the drainage effect is most expected on the basis of preoperative imaging studies. Thus, stent replacement or conversion to a metal stent should be performed in the bile duct where the stent was previously placed [1] [2] [3].
Endoscopic submucosal dissection for superficial nasopharyngeal carcinoma
Authors: Hirohisa Sakurai, Takashi Kanesaka, Tadashi Yoshii, Kosuke Urabe, Takashi Fujii, Tomoki Michida, Ryu Ishihara
Journal: Endoscopy (2022)

Early-stage nasopharyngeal cancer is treated by radiotherapy or chemoradiotherapy [1]. Radiotherapy is less toxic than chemoradiotherapy but has a reported failure rate of 15–30 %. Endoscopic submucosal dissection (ESD) is a minimally invasive treatment for superficial oropharyngeal and hypopharyngeal cancers [2] [3] [4], but it has not been previously performed for nasopharyngeal cancer owing to the difficulty of an endoscopic approach. This case report demonstrates ESD for nasopharyngeal lesions.
Traction method using slim biopsy forceps for prevention of stent migration during multiple biliary stent placement
Authors: Kosuke Iwano, Tsuyoshi Hayashi, Tatsuya Ishii, Kuniyuki Takahashi, Akio Katanuma
Journal: Endoscopy (2022)

Stent migration is a possible complication encountered during placement of multiple biliary stents [1]. The SpyBite Max Biopsy Forceps (Boston Scientific Endoscopy, Natick, Massachusetts, United States), which are very slim biopsy forceps, have been developed for biopsy during peroral cholangioscopy. The forceps are introduced simultaneously from the same working channel of the duodenoscope during placement of the 7-Fr or 8.5-Fr biliary stent. Herein, we present a novel traction technique using SpyBite to prevent stent migration during placement of multiple stents.
Complete resection of residual rectal dysplasia in a patient with ulcerative colitis using the pocket-creation method
Authors: Toshihiro Fujinuma, Takahito Takezawa, Masahiro Okada, Yoshikazu Hayashi, Yusuke Amano, Alan Kawarai Lefor, Hironori Yamamoto
Journal: Endoscopy (2022)

Formerly, when ulcerative colitis-associated neoplasia (UCAN) was identified, total colectomy was required to prevent future colorectal cancers. Since the introduction of the SCENIC guideline (2015) [1], endoscopic resection of UCAN is gradually being accepted. UCANs are however obscurely demarcated and have severe submucosal fibrosis, which makes endoscopic R0 resection challenging. Although multiple biopsies can be helpful to demarcate UCAN, they make the resection more challenging. The pocket-creation method (PCM) of endoscopic submucosal dissection (ESD) is good for resecting fibrotic submucosa, such as that under nongranular laterally spreading tumors [2] or after endoscopic interventions including biopsies. We illustrate the complete endoscopic resection of an area of rectal dysplasia in a patient with UC using the PCM.
Endoscopic closure, involving the muscle layer, of a duodenal post-resection mucosal defect using double-layer suturing assisted by reopenable clips
Authors: Teppei Masunaga, Motohiko Kato, Naohisa Yahagi
Journal: Endoscopy (2022)

Endoscopic double-layered suturing is one of the methods for endoscopic closure. To approximate a mucosal defect, endoscopic clips are applied to the submucosal layer at the center of the long axis of the ulcer [1]. We report a case in which complete closure of the muscle layer of the duodenum was achieved by double-layer suturing assisted by reopenable clips ([Video 1]).
Efficacy of an easy loop-forming guidewire in endoscopic transpapillary gallbladder drainage with gallstones impacted in the cystic duct
Authors: Mamoru Takenaka, Kae Fukunishi, Kota Takashima, Tomohiro Yamazaki, Masatoshi Kudo
Journal: Endoscopy (2022)

Endoscopic transpapillary gallbladder drainage (ETGBD) is a drainage method for acute cholecystitis; it is often used in patients who are on antithrombotic drugs or in those presenting with ascites [1] [2] [3]. However, the success rate of the procedure is lower than that of percutaneous transhepatic biliary drainage (PTGBD), and one of the reasons for this is the difficulty of inserting the guidewire into the gallbladder [4]. Especially in cases where a stone is impacted in the cystic duct, it becomes even more difficult to insert the guidewire into the gallbladder [5].A 75-year-old man with acute cholecystitis had been referred because of septic shock. The patient was taking two antithrombotic drugs. Computed tomography revealed gallbladder wall thickening, gallstones, and fat-stranding around the enlarged gallbladder ([Fig. 1]). Magnetic resonance cholangiopancreatography confirmed the presence of impacted gallstones in the cystic duct ([Fig. 2]). Because of the antithrombotic drugs and the presence of ascites, ETGBD was selected as the drainage method.
On the trail of a ticking bomb: an unusual case of gastrointestinal bleeding in a young adult
Authors: Sarah Klauss, Mark op den Winkel, Jörg Schirra, Markus Rentsch, Julia Mayerle, Jens H. L. Neumann, Enrico N. De Toni
Journal: Endoscopy (2022)

A 21-year-old man presented to our hospital with profuse hematochezia. He reported having been admitted at another hospital 2 years earlier due to a hemoglobin (Hb)-relevant lower gastrointestinal bleed. At that time, the diagnostic workup (including a capsule endoscopy and a red blood cell scintigraphy) failed to reveal the cause of bleeding.
Examination of effectiveness of kinaesthetic haptic feedback for motor imagery-based brain-computer interface training
Authors: Isao Sakamaki, Mahdi Tavakoli, Sandra Wiebe, Kim Adams
Journal: Brain-Computer Interfaces (2022)

Motor imagery-based brain computer interfaces (BCI) performance can be reinforced by visual presentation of feedback about the motor imagery displayed on a screen. However, to directly control robots by the BCI, a different feedback modality may be preferred. The objective of this study was to develop a BCI with kinaesthetic haptic feedback based on the detected motor imagery, and compare its performance to using visual feedback. Twelve online BCI runs with both feedback modalities were performed by ten adults without impairments, and four runs in a game-like task were performed by one adult with cerebral palsy and one child without impairments. The participants completed the BCI training with an average accuracy of 67.28 ± 11.2% for visual feedback and 75.12 ± 12.3% for kinaesthetic haptic feedback. The BCI training with kinaesthetic haptic feedback resulted in less workload and statistically higher classification accuracy than visual feedback (p = 0.03).
Endoscopic closure of the ulcer bed after endoscopic resection using the “mucosal adaptive ring to close an endoscopic artificial ulcer” (MARCEAU) procedure
Authors: Louis-Jean Masgnaux, Clara Yzet, Jean Grimaldi, Timothée Wallenhorst, Jérémie Jacques, Jérôme Rivory, Mathieu Pioche
Journal: Endoscopy (2022)

Endoscopic submucosal dissection (ESD) allows for wide resection of mucosal neoplasms, and closure of the subsequent artificial mucosal defects has been proven to diminish the rate of adverse events. Nevertheless, the technical success rate of such closure is low, around 57 % in large dedicated series [1]. Therefore, several tools and techniques have been described to facilitate the sealing of such ulcers, but none seems to be sufficiently user friendly to be widely used in real-life practice.
EBF1 primes B-lymphoid enhancers and limits the myeloid bias in murine multipotent progenitors
Authors: Aurelie Lenaerts, Iwo Kucinski, Ward Deboutte, Marta Derecka, Pierre Cauchy, Thomas Manke, Berthold Göttgens, Rudolf Grosschedl
Journal: The Journal of Experimental Medicine (2022)

Hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) generate all cells of the blood system. Despite their multipotency, MPPs display poorly understood lineage bias. Here, we examine whether lineage-specifying transcription factors, such as the B-lineage determinant EBF1, regulate lineage preference in early progenitors. We detect low-level EBF1 expression in myeloid-biased MPP3 and lymphoid-biased MPP4 cells, coinciding with expression of the myeloid determinant C/EBPα. Hematopoietic deletion of Ebf1 results in enhanced myelopoiesis and reduced HSC repopulation capacity. Ebf1-deficient MPP3 and MPP4 cells exhibit an augmented myeloid differentiation potential and a transcriptome with an enriched C/EBPα signature. Correspondingly, EBF1 binds the Cebpa enhancer, and the deficiency and overexpression of Ebf1 in MPP3 and MPP4 cells lead to an up- and downregulation of Cebpa expression, respectively. In addition, EBF1 primes the chromatin of B-lymphoid enhancers specifically in MPP3 cells. Thus, our study implicates EBF1 in regulating myeloid/lymphoid fate bias in MPPs by constraining C/EBPα-driven myelopoiesis and priming the B-lymphoid fate.
Notch1 Induces Defective Epithelial Surfactant Processing and Pulmonary Fibrosis
Authors: Roxana Wasnick, Martina Korfei, Katarzyna Piskulak, Ingrid Henneke, Jochen Wilhelm, Poornima Mahavadi, Ruth Charlotte Dartsch, Daniel von der Beck, Miriam Koch, Irina Shalashova, Astrid Weiss, Oleksiy Klymenko, Ingolf Askevold, Ludger Fink, Heiko Witt, Holger Hackstein, Elie El Agha, Saverio Bellusci, Walter Klepetko, Melanie Königshoff, Oliver Eickelberg, Ralph Theo Schermuly, Thomas Braun, Werner Seeger, Clemens Ruppert, Andreas Guenther
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Although type II alveolar epithelial cells (AEC2s) are chronically injured in idiopathic pulmonary fibrosis (IPF), they contribute to epithelial regeneration in IPF. Objectives: We hypothesized that Notch signaling may contribute to AEC2 proliferation, dedifferentiation characterized by loss of surfactant processing machinery, and lung fibrosis in IPF. Methods: We applied microarray analysis, kinome profiling, flow cytometry, immunofluorescence analysis, western blotting, quantitative PCR, and proliferation and surface activity analysis to study epithelial differentiation, proliferation, and matrix deposition in vitro (AEC2 lines, primary murine/human AEC2s), ex vivo (human IPF-derived precision-cut lung slices), and in vivo (bleomycin and pepstatin application, Notch1 [Notch receptor 1] intracellular domain overexpression). Measurements and Main Results: We document here extensive SP-B and -C (surfactant protein-B and -C) processing defects in IPF AEC2s, due to loss of Napsin A, resulting in increased intra-alveolar surface tension and alveolar collapse and induction of endoplasmic reticulum stress in AEC2s. In vivo pharmacological inhibition of Napsin A results in the development of AEC2 injury and overt lung fibrosis. We also demonstrate that Notch1 signaling is already activated early in IPF and determines AEC2 fate by inhibiting differentiation (reduced lamellar body compartment, reduced capacity to process hydrophobic SP) and by causing increased epithelial proliferation and development of lung fibrosis, putatively via altered JAK (Janus kinase)/Stat (signal transducer and activator of transcription) signaling in AEC2s. Conversely, inhibition of Notch signaling in IPF-derived precision-cut lung slices improved the surfactant processing capacity of AEC2s and reversed fibrosis. Conclusions: Notch1 is a central regulator of AEC2 fate in IPF. It induces alveolar epithelial proliferation and loss of Napsin A and of surfactant proprotein processing, and it contributes to fibroproliferation.
A root cause analysis system to establish the most plausible explanation for post-endoscopy upper gastrointestinal cancer
Authors: Umair Kamran, Dominic King, Abdullah Abbasi, Ben Coupland, Nosheen Umar, Warren C. Chapman, Srisha Hebbar, Nigel J. Trudgill
Journal: Endoscopy (2022)

BACKGROUND : Missing upper gastrointestinal cancer (UGIC) at endoscopy may prevent curative treatment. We have developed a root cause analysis system for potentially missed UGICs at endoscopy (post-endoscopy UGIC [PEUGIC]) to establish the most plausible explanations. METHODS : The electronic records of patients with UGIC at two National Health Service providers were examined. PEUGICs were defined as UGICs diagnosed 6-36 months after an endoscopy that did not diagnose cancer. An algorithm based on the World Endoscopy Organization post-colonoscopy colorectal cancer algorithm was developed to categorize and identify potentially avoidable PEUGICs. RESULTS : Of 1327 UGICs studied, 89 (6.7 %) were PEUGICs (patient median [IQR] age at endoscopy 73.5 (63.5-81.0); 60.7 % men). Of the PEUGICs, 40 % were diagnosed in patients with Barrett's esophagus. PEUGICs were categorized as: A - lesion detected, adequate assessment and decision-making, but PEUGIC occurred (16.9 %); B - lesion detected, inadequate assessment or decision-making (34.8 %); C - possible missed lesion, endoscopy and decision-making adequate (8.9 %); D - possible missed lesion, endoscopy or decision-making inadequate (33.7 %); E - deviated from management pathway but appropriate (5.6 %); F - deviated inappropriately from management pathway (3.4 %). The majority of PEUGICs (71 %) were potentially avoidable and in 45 % the cancer outcome could have been different if it had been diagnosed on the initial endoscopy. There was a negative correlation between endoscopists' mean annual number of endoscopies and the technically attributable PEUGIC rate (correlation coefficient -0.57; P = 0.004). CONCLUSION : Missed opportunities to avoid PEUGIC were identified in 71 % of cases. Root cause analysis can standardize future investigation of PEUGIC and guide quality improvement efforts.